Classifications

• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
  • B29C—SHAPING OR JOINING OF PLASTICS; SHAPING OF MATERIAL IN A PLASTIC STATE, NOT OTHERWISE PROVIDED FOR; AFTER-TREATMENT OF THE SHAPED PRODUCTS, e.g. REPAIRING
  • B29C49/00—Blow-moulding, i.e. blowing a preform or parison to a desired shape within a mould; Apparatus therefor
  • B29C49/18—Blow-moulding, i.e. blowing a preform or parison to a desired shape within a mould; Apparatus therefor using several blowing steps
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/5545—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having eight-membered rings not containing additional condensed or non-condensed nitrogen-containing 3-7 membered rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/08—Bridged systems
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
  • B29C—SHAPING OR JOINING OF PLASTICS; SHAPING OF MATERIAL IN A PLASTIC STATE, NOT OTHERWISE PROVIDED FOR; AFTER-TREATMENT OF THE SHAPED PRODUCTS, e.g. REPAIRING
  • B29C49/00—Blow-moulding, i.e. blowing a preform or parison to a desired shape within a mould; Apparatus therefor
  • B29C49/02—Combined blow-moulding and manufacture of the preform or the parison
  • B29C49/04—Extrusion blow-moulding

Definitions

• This invention relates to new heterocyclic compounds and process for preparing the same.
• the compounds of the invention are 3,8-diazabicyclo-[3,2,1]-octanes of the formula:
• R represents hydrogen, lower alkyl, aryl and aralkyl, R represents hydrogen, or methyl.
• 3-benzyl-8-methyl- 3-8-diazabicyclo-[3,2,1]-octane methiodide has analgetic properties and increases in mice the stimulus threshold (expressed in mm. Hg as pressure applied to the excited member, according to the Randall and Selitto procedure) of +23 at the doses of 2 mg./kg. and of +48 at 5 mg./kg.
• 3-cinnamyl-8- methyl-3 ,8-diazabicyclo- 3 ,2,1]-octane increases urinary excretion by about 170 percent at 10 mg./ kg. and sodium excretion by over 120 percent at 10 mg./kg. and by 180 percent at 25 mg./ kg. in mice.
• the process of the invention consists in adding an ether solution of 3,8-diazabicyclo-[3,2,l]-octane-2,4-dione of the formula:
• the internal anhydride of the carbobenzoxypyrrolidine- 2,5-dicarboxylic acid (I) is prepared by hydrogenating 2,5-dicarbethoxy-N-benzylpyrrolidine under a pressure of about 20 atmospheres, using palladium on charcoal catalyst, hydrolysing the 2,5-dicarbethoxypyrrolidine (VI) thus obtained by refluxing the aqueous suspension separating the acid (VII) by concentrating the clear resulting solution and then treating it with the appropriate reagent, such as benzyl chlorocarbonate.
• Pyrrolidine-2,5-a'icarboxylic acid A suspension of 200 g. of 2,5-dicarbethoxypyrrolidine in 8 1. H O is refluxed for 25-30 hours.
• N-carbobenzoxypyrrolidine-2,5-dicarb0xylic acid To a solution of 67 g. of pyrrolidine 2,5-dicarboxylic acid in 420 ml. 2 N NaOH, cooled to 8-10 C. are added with vigorous stirring 73 g. of benzyl chlorocarbonate together with 210 ml. 2 N NaOH over a period of 30 minutes. The solution is stirred for 2 hours at room temperature, then it is extracted with ethyl ether and the aqueous phase is acidified with concentrated HCl. An oil separates which is extracted with ethyl ether and the evaporated ether extract gives an oil that solidifies in vacuo in a short time. Yield 86.5 g. (64.5%), M.P. 125- 127 C.
• N -car,bobenz0xy pyrrolidine-2,5 -a'icarb0xy lic acid anhydride A solution of 79 g. of N-carbobenzoxypyrrolidine-Z,5- dicarboxylic acid in 360 ml. acetic anhydride is refluxed for 1 hour, then it is evaporated to dryness; the residue is heated for '1 hour at 14 C. under 1 mm. pressure. The residue is then cooled, taken up in ml. warm ethyl ether which dissolves the coloured impurities and the anhydride is collected by filtering in vacuo. Yield 58.1 g. (78% M.P. 166-168" C.
• the resulting crude monoamide is refluxed with 5 portions of its weight of acetic anhydride for 1 hour.
• the mixture acetic acid-acetic anhydride is distilled in vacuo and heated for :1 hour at 130-140 C. under 1 anrn. pressure till the reaction is complete.
• the residue is then taken up with 300 ml. ethyl ether and the insoluble portion is removed. After drying over Na SO the solvent is removed and the product is purified by distillation. Yield 1'8 g. (66%), M.P. C.
• EXAMPLE 2 3-methyl-8-carbobenz0xy-3,8-diazabicycl0- [3,2,1 -0ctane- 2,4-dione
• S-dicarboxylic acid anhydride in 300 ml. anhydrous benzol 3.42 g. of methylamine are added with cooling.
• the solution is refluxed for 30 minutes, the solvent is removed in vacuo and the obtained crude monoamide is refiuxed with 5 portions of its weight of acetic anhydride for 1 hour.
• the main solvent is distilled in vacuo and the reaction is completed by heating at l40 C. for 1 hour under 1 mm. pressure.
• EXAMPLE 10 2 -benzy lcarbamyl-S -carbeth oxy-pyrrolidine A mixture of 21.5 g. of 2,5-dicarbethoxypyrrolidine and 11.8 g. of benzylamine in 50 ml. of anhydrous xylene is refluxed for 24 hrs; the main part of the organic solvent is removed, the 2,S-dibenzylcarbamyl-pyrrolidine that precipitates from the concentrated solution is filtered off, and after removing the solvent the residue is distilled in vacuo. Yield 20.2 g. (72.5%),. B.P. 178180 C./0.3 mm. An elemental analysis gave C, 65,38 percent; H, 7.19 percent; N, 10.33 percent. Calcd. for C H N O C, 65.21 percent; H, 7.24 percent; N, 10.14 percent.
• a compound of the class consisting of a 3,8-diazabicyclo-[3,2,1]-octane of the formula:
• R is a member of the class consisting of hydrogen, lower alkyl, phenyl, cinnamyl, benzyl and chlorobenzhydryl, R is a member of the class consisting of hydrogen and methyl and its quaternary non-toxic addition salts.
• X is a member of the class consisting of hydrogen and carbobenzoxy and R is a member of the class consisting of hydrogen, lower alkyl, phenyl, cinnamyl, benzyl and chlorobenzhydryl, which comprises reacting a compound of the formula:
• CHzGH-C O wherein X has the above significance, with an excess of an amine of the formula NH R wherein R has the above significance, in an inert anhydrous organic solvent and refluxing the obtained monoamide with acetic anhydride.
• CH2-CHCO 1TTX III-R CHzCH-CO wherein X is a member of the class. consisting of hydrogen and carbobenzoxy and R is a member of the class consisting of hydrogen, lower alkyl, phenyl, cinnamyl, benzyl and chlorobenzhydryl.
• NICHOLAS S. RIZZO Primary Examiner.

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Cited By (3)

• 1961
  • 1961-02-10 CH CH163161A patent/CH404678A/de unknown
  • 1961-02-10 CH CH702061A patent/CH408036A/de unknown
  • 1961-02-16 DE DE19611445094 patent/DE1445094A1/de active Pending
  • 1961-02-16 DE DEL46485A patent/DE1200316B/de active Pending
  • 1961-04-19 US US104016A patent/US3221015A/en not_active Expired - Lifetime

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